Extra cellular matrix derived metabolite regulates angiogenesis by FasL mediated apoptosis.
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ABSTRACT: OBJECT: Antiangiogenic treatments are beginning to give promising outcomes in many vascular diseases including tumor angiogenesis. In this current study the antiangiogenic and pro-apoptotic actions of ?1(IV)NC1 and its N- and C- peptides ?1S1(IV)NC1, ?1S2(IV)NC1 were investigated in-vitro and in-vivo. STUDY METHOD: Endothelial cells (ECs) were treated with ?1(IV)NC1, ?1S1(IV)NC1, ?1S2(IV)NC1 and in-vitro proliferation, migration, tube formation and apoptotic assays were executed. FasL, Fas, Caspase-8, -3 and PARP activations were studied using immunoblotting analysis using specific antibodies. Also the in-vivo antiangiogenic and pro-apoptotic effects were tested using ?1(IV)NC1 in a mice model. RESULTS: Like ?1(IV)NC1, its N- and C- terminal ?1S2(IV)NC1 and ?1S1(IV)NC1 domains posses anti-proliferative, pro-apoptotic activity and inhibit ECs migration and tube formation in-vitro. Both ?1S1(IV)NC1 and ?1S2(IV)NC1 domains promote apoptosis by activating FasL and down stream apoptotic events including activation of caspase-8, -3 and PARP cleavage in a dose dependent manner in-vitro in ECs. Tumors in mice showed apoptotic TUNEL positive microvasculature upon ?1(IV)NC1 treatment, indicating inhibition of tumor angiogenesis and tumor growth. Further, the antitumor activity of ?1(IV)NC1 was abrogated when caspase-3 inhibitor was used. These results conform additional properties of ?1(IV)NC1 as an endogenous angioinhibitor that induces apoptosis in-vitro and in-vivo by activating FasL mediated caspase-3. SIGNIFICANCE: ?1(IV)NC1 and its N- and C- terminal ?1S1(IV)NC1 and ?1S2(IV)NC1 domains also posses pro-apoptotic and angioinhibitory activity in-vitro and in-vivo. ?1(IV)NC1 regulates tumor angiogenesis by activating FasL mediated apoptosis in-vitro and in-vivo. These results demonstrate that ?1(IV)NC1 and its peptides inhibit neo-vascular diseases.
SUBMITTER: Verma RK
PROVIDER: S-EPMC3851695 | biostudies-other | 2013
REPOSITORIES: biostudies-other
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